1. Field of the Invention
The invention relates to a process for the preparation of hydroxy and amino compounds.
2. Background Art
The reaction of reactive halogen compounds, in particular xcex1-halocarbonyl compounds, with electrophilic substrates in the presence of zinc metal is known as Reformatsky reaction. Examples of electrophilic substrates include aldehydes, ketones, imines, nitriles, carboxylic anhydrides, carbonyl chlorides, lactones, orthoformates, formates, epoxides, azirines, aminals and nitrones. The reaction is important for the synthesis of building blocks for the preparation of pharmaceutical active ingredients, fragrances and crop protection compositions.
The choice of solvent, the method of activation of the zinc used, and in general the nature of overall reaction mixture, are of decisive importance for achieving good yields and high selectivities, and thus high product purity.
Particularly suitable solvents for the Reformatsky reaction are ethers such as diethyl ether, 1,4-dioxane, dimethoxymethane, dimethoxyethane and, in particular, tetrahydrofuran. In addition, other solvents which have proven effective are aromatic hydrocarbons or mixtures of the abovementioned ethers with aromatic hydrocarbons, mixtures of tetrahydrofuran and trimethyl borate, and the polar solvents acetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and hexamethylphosphoric triamide. A useful summary of the reaction may be found in A. Fxc3xcrstner, SYNTHESIS 1989, p. 571. European published application EP-A-562 343 discloses that the reaction of xcex1-bromocarboxylic esters with carbonyl compounds in the presence of zinc in methylene chloride solvent proceeds with high yields. However, the use of the foregoing solvents or solvent mixtures have numerous disadvantages.
The water-miscible ethers 1,4-dioxane and tetrahydrofuran, and the water-miscible polar solvents acetonitrile, dimethylformamide, dimethylacetamide, dimethyl sulfoxide and hexamethylphosphoric triamide, dissolve during aqueous hydrolysis of the zinc compounds and zinc salts formed in the aqueous phase. For economical reasons and to reduce the amounts of waste, particularly in industrial scale processes, recovery of the solvents from the aqueous phase, e.g. by extraction or distillation, is necessary. This recovery, however, is expensive, and adds considerable cost to the process.
In addition, in the case of the use of the abovementioned water-miscible solvents for the hydrolysis of the reaction mixture, it is usually necessary to use a water-immiscible organic solvent, such as ethyl acetate or methyl tert-butyl ether as cosolvents, to improve phase separation. These solvents must also be recovered and freed from impurities by distillation prior to reuse, again, an expensive process. If solvent mixtures are used for Reformatsky reactions, the recovery, separation and optional purification of the individual solvents used generally requires further expense.
Use of diethyl ether, 1,4-dioxane, dimethoxymethane, dimethoxyethane and tetrahydrofuran as solvents for Reformatsky reactions is further disadvantageous, as these ether solvents have a tendency, as a result of autoxidation, to form explosive peroxides. This tendency to produce peroxides makes the use of such solvents hazardous on an industrial scale. When recovery and repeated use is contemplated, their use is yet more difficult, or possible only with large expenditure, due to the danger of accumulation of explosive constituents.
The use of methylene chloride as a solvent as taught by EP-A-562 343, or the use of other halogenated hydrocarbons is unacceptable for reasons of environmental concerns, and should therefore be avoided, particularly on an industrial scale. In addition, many of the abovementioned solvents are expensive, which additionally adversely affects the economy of the reaction unless the solvent is recovered.
There was therefore still a need for a suitable solvent for the reaction of electrophilic substrates such as aldehydes, ketones and imines with reactive halogen compounds in the presence of zinc, which allows the reaction, particularly on an industrial scale, to be carried out in an environmentally responsible and cost-effective manner, without the use of solvent mixtures or the addition of cosolvents. Coupled with the use of such solvent should be the simplest possible recovery method for the solvent, thus allowing reduction in the amounts of waste. However, the solvent should not lower the yield and selectivity compared with previously known solvents.
The invention provides a process for the preparation of hydroxy and amino compounds, in which, in a first step, aldehydes, ketones or imine electrophiles are reacted in a Reformatsky reaction with a reactive halogen compound and zinc in carboxylic esters as solvents, the reactive halogen compound being brought into contact with the zinc at the same time as or after contact with the aldehydes, ketones or imines; and, in a second step, the reaction product of the first step is hydrolyzed.
Preference is given to a process for the preparation of hydroxy and amino compounds of the general formula (1)
R1R2C(Wx)xe2x80x94R3R4Cxe2x80x94(X)axe2x80x94Yxe2x80x83xe2x80x83(1) 
comprising reacting, in a first step, aldehydes, ketones or imines of the general formula (2)
xe2x80x83R1R2Cxe2x95x90Wxe2x80x83xe2x80x83(2)
with zinc and reactive halogen compounds of the general formula (3)
Halxe2x80x94R3R4Cxe2x80x94(X)axe2x80x94Yxe2x80x83xe2x80x83(3), 
in a carboxylic ester solvent of the general formula (4)
R5xe2x80x94((O(CH2)m)nxe2x80x94COOxe2x80x94((CH2)oxe2x80x94COO)pxe2x80x94((CH2)qO)rxe2x80x94R6xe2x80x83xe2x80x83(4), 
where
R1 and R2 are hydrogen or an optionally halogen- or cyano-substituted C1-C30-hydrocarbon radical in which one or more nonadjacent methylene units can be replaced by xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, or xe2x80x94OCOOxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NRx-groups and in which one more methine units can be replaced by xe2x80x94Nxe2x95x90 or xe2x80x94Pxe2x95x90 groups,
Wx is OH or NHR1,
W is O or NR1,
R3 and R4 are independently hydrogen, halogen or an optionally halogen-substituted C1-C30-hydrocarbon radical in which one or more nonadjacent methylene units can be replaced by xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, or xe2x80x94OCOOxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NRx-groups and in which one more methine units can be replaced by xe2x80x94Nxe2x95x90 or xe2x80x94Pxe2x95x90 groups,
X is chosen from 
a is an integer with a value of 0 or 1,
Y is CN, (Cxe2x95x90O)xe2x80x94Z, (SO2)xe2x80x94Z, (Pxe2x95x90O)(xe2x80x94Z)2 or an aromatic radical, where one or more methine units in the ring can be replaced by xe2x80x94Nxe2x95x90 or xe2x80x94Pxe2x95x90 groups, and the ring can carry the hetero atoms xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94, where the aromatic ring is optionally halogen- or cyano-substituted or substituted by C1-C30-hydrocarbon radicals in which one or more nonadjacent methylene units can be replaced by xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, or xe2x80x94OCOOxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NRx-groups,
Z is an optionally halogen-substituted C1-C30-hydrocarbon radical in which one or more nonadjacent methylene units can be replaced by xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, or xe2x80x94OCOOxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94NRx-groups and in which one or more methine units can be replaced by xe2x80x94Nxe2x95x90 or xe2x80x94Pxe2x95x90 groups, OH, OR1, OSi(R1)3, NHR1 or NR1R2,
Hal is chlorine, bromine or iodine,
R5 and R6 are independently C1-C30-hydrocarbon radicals in which one or more nonadjacent methylene units can be replaced by xe2x80x94Oxe2x80x94 groups,
Rx is hydrogen or an optionally halogen-substituted C1-C30-hydrocarbon radical in which one or more nonadjacent methylene units can be replaced by xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94OCOxe2x80x94, or xe2x80x94OCOOxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NCH3xe2x80x94 groups and in which one or more methine units can be replaced by xe2x80x94Nxe2x95x90 or xe2x80x94Pxe2x95x90 groups,
m, n, o, p, q and r are integers with a value of from 0 to 6, where in each case 2 radicals chosen from the pairs R1 and R2, R3 and R4, R1 and R3, R1 and Y, R1 and Z, R3 and Y, R3 and Z, Wx and Y, and Wx and Z, where Wx is Oxe2x80x94 or NR1- and Z can also be a direct bond, are linked together,
where the reactive halogen compounds of the general formula (3) are brought into contact with the zinc at the same time as the compounds of the general formula (2) are brought into contact with zinc, or at a later time, and in a second step, hydrolyzing the reaction product of the first step.
Hydroxy and amino compounds of the general formula (1) can be prepared by the process according to the invention described above in very high yields, i.e. up to 90% or more, and at very high purities, in a simple manner and with very good space-time yields.
The process according to the invention has proven to be particularly simple on an industrial scale since the reaction can be carried out in commercially available carboxylic ester solvents of the general formula (4) without any pretreatment of these solvents, for example, distillation or drying, and neither the addition of a further solvent for carrying out the reaction or for the work-up, or a cosolvent for improved phase separation during work-up is required. Since no solvent mixtures are required, recovery of solvent has proven to be very straightforward. The preferred carboxylic esters of the general formula (4) have low solubility or dissolve only very slightly in water and can therefore be recovered easily and efficiently, for example during product isolation, making the reaction very economical. Thus, for example, ethyl acetate, isopropyl acetate or butyl acetate as solvents of the general formula (4) can be recovered during isolation of the prepared products by distillation, in very high yields.
As a result of the replacement of halogen-containing hydrocarbons and ether solvents sensitive to peroxide formation with carboxylic esters of the general formula (4), the process of the invention is not only more environmentally friendly, but is also associated with a significantly reduced hazard potential. In addition, the product yield and product quality of the hydroxy and amino compounds of the general formula (1) prepared by the process of the invention, are in many cases, improved as compared with previously known processes described in the literature. The use of carboxylic esters of the general formula (4) is, for the course of the reaction, for the product yields and purities, and for the elimination of secondary reactions, of particular advantage. In addition, in most cases it is possible to carry out the inventive process using a relatively low excess of zinc and reactive halogen compound of the general formula (3) based on the electrophilic reactants, the product yield and quality in many cases still being higher than when previously known solvents are used, which makes the process according to the invention yet more economical.
In the process according to the invention, preference is given to first introducing zinc and aldehyde, ketone or imine of the general formula (2) into the carboxylic ester of the general formula (4), and then adding the reactive halogen compound of the general formula (3), optionally dissolved in a solvent.
It is alternatively preferred to initially introduce zinc into the carboxylic ester of the general formula (4) and then to add a mixture of reactive halogen compound of the general formula (3) and aldehyde, ketone or imine of the general formula (2), optionally dissolved in a solvent.
From E. W. Warnhoff, M. Y. H. Wong, P. S. Raman, CAN. J. CHEM. 1981, 59, p. 688 it is known that xcex1-halogenozinc carbonyl compounds (Reformatsky reagents) of the general formula (3), where Hal is halogenozinc, can react with carboxylic esters as electrophiles. It is believed that since aldehydes, ketones and imines are more electrophilic and thus more reactive than carboxylic acid derivatives such as the carboxylic ester solvents of the general formula (4), the former react preferably and more rapidly with halogenozinc carbonyl compounds of the general formula (3) (Reformatsky reagents) than the carboxylic ester solvents.
If zinc is first introduced into the carboxylic ester of the general formula (4), following which the reactive halogen compound of the general formula (3) is added and finally the electrophile is added, then the reaction would be expected to proceed with the formation of undesired by-products. For this reason, carboxylic esters of the general formula (4) have hitherto not been used as solvents for the reaction of aldehydes, ketones and imines with reactive halogen compounds and zinc or for the production of halogenozinc carbonyl compounds of the general formula (3) (Reformatsky reagents), where Hal is halogenozinc.
The C1-C30-hydrocarbon radicals for R1, R2, R3, R4 and Z are preferably linear, branched or cyclic C1-C20-alkyl, C2-C20-alkenyl, C5-C20-acetalalkenyl, or C3-C20-alkoxycarbonylalkyl radicals, optionally substituted by F, Cl, Br, I, CN and C1-C8-alkoxy radicals; aryl, aralkyl, alkaryl, aralkenyl, alkenylaryl radicals in which one or more methine units may be replaced by xe2x80x94Nxe2x95x90 or xe2x80x94Pxe2x95x90 groups and methylene units may be replaced by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, and optionally substituted by F, Cl, Br, I, CN and C1-C10-alkoxy radicals, and which optionally carry C1-C10-alkyl radicals on the ring and optionally hetero atoms xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94 in the ring.
The radicals R1 and R2, R3 and R4, R1 and R3, R1 and Y, R1 and Z, R3 and Y, R3 and Z, Wx and Y and Wx and Z, where Wx is Oxe2x80x94or NR1- and Z can also be a direct bond, or can be linked together to form a variety of ring structures when such linkages are possible. The radicals R1 and R3, R1 and Y, R1 and Z, Wx and Y, and Wx and Z, where Wx is Oxe2x80x94 or NR1- and Z can be a direct bond, can, for example, be linked together by intramolecular reaction.
When R3 and R4 are halogen radicals, they are preferably F and Cl. In particular, a has the value 0.
As reactive halogen compounds of the general formula (3), preference is given to using bromine compounds, where Hal in the general formula (3) is bromine. Preference is given to reactive halogen compounds of the general formula (3) in which Y is (Cxe2x95x90O)xe2x80x94Z. Also preferred are reactive halogen compounds of the general formula (3) in which Z is OR1. Particularly preferred reactive halogen compounds of the general formula (3) are xcex1-bromocarboxylic esters.
Zinc is preferably used in the form of films, ribbon, pieces, powder, or dust form, or in the form of zinc wool. The presence of other metals such as copper, silver or mercury is not required. Most preferably, zinc is used in the form of commercially available, standard commercial zinc powder or zinc dust.
To achieve higher product yields, it has proven useful to activate the zinc prior to the addition of the aldehyde, ketone or imine of the general formula (2) and the reactive halogen compound of the general formula (3) or mixture thereof. For zinc activation, previously known methods which are customarily used and are given, for example, in the summary by A. Fxc3xcrstner, SYNTHESIS 1989, p. 571, are suitable. Methods which have proven quite successful are washing of the zinc with acid, activation by iodine, as described in EP-A-562 343, and activation by trimethylchlorosilane, the activation by trimethylchlorosilane being particularly preferred because it is simple to carry out and because of increased yields, product purities and selectivities, and suppression of secondary reactions. The activation of zinc by trimethylchlorosilane in the diethyl ether solvent is known from G. Picotin, P. Miginiac, J. ORG. CHEM. 1987, 52, p. 4796.
For activation of zinc with trimethylchlorosilane, zinc is introduced into the carboxylic ester of the general formula (4), then trimethylchlorosilane is added and the mixture is heated for 10 min to 2 h, preferably 10 to 45 min, at temperatures of from 30 to 150xc2x0 C., preferably at 40 to 120xc2x0 C., and more preferably at 50 to 90xc2x0 C. It has proven successful to react the zinc with trimethylchlorosilane in the carboxylic ester of the general formula (5) in a molar ratio of 1:(0.01 to 0.5), in particular 1:(0.05 to 0.3) accompanied by heating to the desired temperature.
In the carboxylic esters of the general formula (4), R5 and R6 are preferably straight-chain, branched or cyclic C1-C10-alkyl, C6-C10-aralkyl, C2-C10-alkoxyalkyl radicals or C5-C10-aryl radicals. In particular, R5 and R6 are straight-chain or branched C1-C8-alkyl radicals. The subscripts m, n, o, p, q and r are preferably integers with a value of 0, 1, 2 or 3. In particular, n, p and r are 0.
Particularly preferred carboxylic esters of the general formula (4) are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-hexyl, n-pentyl, and i-pentyl esters of acetic acid, propionic acid and butyric acid and mixed C6-14 alkyl acetates. The esters and the acetic alkyl acetate mixtures can be recovered in very high yield during isolation of the products, and subsequently reused. If the cost-effective methyl acetate is used as solvent of the general formula (4), it is possible to dispense with a recovery step.
For the activation of the reaction mixture, it is also possible to use additives such as compounds of copper, chromium, manganese, cobalt, bismuth, samarium, scandium, indium, titanium, cerium, tellurium, tin, lead, antimony, germanium, aluminum, magnesium, palladium, nickel and mercury, or, where appropriate, mixtures thereof.
During the reaction in the first step, the temperature of the exothermic reaction is preferably maintained at a designated value, where necessary by cooling. The upper temperature limit may be regulated by the boiling point of the solvent of the general formula (4) used, such as, for example ethyl acetate (b.p.: 77xc2x0 C.) or isopropyl acetate (b.p.: 87-89xc2x0 C.). In the case of higher-boiling solvents of the general formula (4), such as, for example, n-butyl acetate (b.p.: 124-126xc2x0 C.), the temperature of the reaction is preferably controlled by cooling. The reaction is preferably carried out at temperatures of from xe2x88x9220 to 150xc2x0 C., more preferably at 20 to 110xc2x0 C., and in particular at 40 to 90xc2x0 C.
The pressure range of the reaction is not critical and can be varied within wide limits. The pressure is usually 0.01 to 20 bar, and preference is given to carrying out the reaction under atmospheric pressure. The reaction is preferably performed without blanketing with protective gas such as nitrogen or argon, although such blanketing can be performed if desired. The reaction can be carried out continuously or batchwise, preferably batchwise.
When the addition of all participating constituents is complete, the reaction is preferably xe2x80x9cpost-reactedxe2x80x9d for a further 5 min to 3 h, more preferably 5 min to 1.5 h, and in particular 5 to 30 min, in order to complete the reaction. Excess zinc metal can be separated off by filtration. It is also possible to dissolve excess zinc in the acid used in the second step for the hydrolysis of the reaction mixture.
It has proven successful to react the zinc with the reactive halogen compound of the general formula (3) and the electrophile of the general formula (2) in the molar ratio (1 to 3):(1 to 2):1, in particular (1.1 to 1.7):(1 to 1.3):1.
The process according to the invention has proven advantageous compared with previously known processes, since in most cases the post-reaction time of 5 to 30 min is considerably shortened. As a result, particularly on an industrial scale, very good space-time yields and thus high efficiency is obtained. Very short post-reaction times arise, in particular, following activation of the reaction mixture or of the zinc by trialkylchlorosilane in the carboxylic ester solvent.
After the reaction in the first step has taken place, the reaction mixture is hydrolyzed in the second step, generally at temperatures of from xe2x88x9230 to 60xc2x0 C., more preferably from xe2x88x9210 to 30xc2x0 C., by the addition of an aqueous acid or base, as a result of which zinc compounds and zinc salts dissolve. Alternatively, the reaction mixture can be added to an aqueous acid or base. Preferred bases are ammonia and organic amines such as trialkylamines and alkanolamines.
Preferred acids are Brxc3x6nstedt acids, in particular strong acids, such as boric acid, tetrafluoroboric acid, nitric acid, nitrous acid, phosphoric acid, phosphorous acid, hypophosphorous acid, sulfuric acid, sulfurous acid, peroxysulfuric acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, hydrobromic acid, perchloric acid, hexafluorophosphoric acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, and trifluoromethanesulfonic acid; and carboxylic acids such as chloroacetic acid, trichloroacetic acid, acetic acid, acrylic acid, benzoic acid, trifluoroacetic acid, citric acid, crotonic acid, formic acid, fumaric acid, maleic acid, malonic acid, gallic acid, itaconic acid, lactic acid, tartaric acid, oxalic acid, phthalic acid and succinic acid.
In particular, ammonia, hydrochloric acid, sulfuric acid or citric acid, preferably ammonia, hydrochloric acid or citric acid, are used. The acid or base may be used in concentrated form or in the form of a dilute aqueous solution.
The products of the general formula (1) can be isolated by known, customarily used methods, such as extraction, distillation, crystallization, or by means of chromatographic methods. In most cases, the crude product obtained following removal of the solvent is of very high purity or of adequate purity and can be used directly in subsequent reactions and conversions, in particular ester hydrolyses.
All of the above symbols in the formulae above have their meanings independently of one another. The term xe2x80x9caxe2x80x9d means xe2x80x9cone or morexe2x80x9d unless indicated otherwise. In the examples below, unless stated otherwise, all amounts and percentages are based on the weight, all pressures are 0.10 MPa (abs.) and all temperatures are 20xc2x0 C.